18-nor-cortisones and process for their preparation



3,@33,853 Patented May 8, 1962 3,033,863 18-NOR-CORTISONES AND PRGCESS FOR THEE PREPARATEGN Gaston Amiard, Noisy-ie-Sec (Seine), and Rene Heymes,

Romainville (Seine), France, assignors, by mesne assignments, to Roussel-UCEAF, .A., Paris, France, a

corporation of France No Drawing. Filed (Set. 10, 1961, Ser. No. 144,836 Claims priority, application France Get. 2t), 1969 14 Claims. (Cl. 260-23955) The invention relates to novel 16a-methyl-18-norcortisones having the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms. The invention further relates to a novel process for the preparation of said compounds and novel intermediates thereof.

Compounds such as cortisone, hydrocortisone, prednisone, prednisolone and dexarnethasone are known to possess glucocorticoidal activity, but it is also known that these products when administered over a period of time have undesirable side efiects such as the retention of sodium and water and are ulcergenic. The compounds of Formula I possess glucocorticoidal activity with a minimum of side efiects.

It is an object or" the invention to provide novel 18- nor-cortisones of Formula I.

It is another object of the invention to provide a novel process for the preparation of 18-nor-cortisones of Formula I.

It is a further object of the invention to provide novel intermediates for ls-nor-cortisones of Formula I and particularly:

(a) 3-ethylenedioxy-l7a-hydroperoxy 16cc methyl- 18-nor-pregnane-1 1,20-dione (b) 3-ethylenedioxy-16a-methyl-18-nor-pregnane-l7aol-l1,20-dione (c) 16a-methy1-18-nor-pregnane-17u-ol-3,11,20-trione (d) 4B-bromo 16a methyl-18-nor-pregnane-1h-ol- 3,11,20-trione (e) 16u-methyl 18 nor-A -pregnene-17x-0l-3,11,20- trione.

These and other objects and advantages will become obvious from the following detailed description.

The compounds of the invention have the formula CH2OR '--on i-CH I wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

The acyl radical of the organic carboxylic acid having 1 to 18 carbon atoms may be derived from an aliphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid. Examples of suitable acids are alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, fl-trimethyl propionic acid, heptanoic acid, caprylic acid, pelarginic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid; cyc-loalkyl alkanoic acids such as cyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids such as phenyl acetic acid and phenyl propionic acid; aryl carboxylic acids such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy acetic acid, p-chlorophenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4- ter-butylphenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids such as furane-Z-carboxylic acid, S-ter-butylfurane-Z- carboxylic acid, 5-bromofurane-2-carboxylic acid and nicotinic acids; ,B-ketoalkanoic acids, such as acetylacetic acid, propionylacetic acid and butyrylacetic acid; amino acids such as diethylaminoacetic acid and aspartic acid.

The 16ot-methyl-18-nor-cortisone and its esters are prepared by reacting 3-ethylenedioxy-16a-methyl-18-norpregnane-11,20-dione with oxygen in the presence of an alkali metal tertiary butylate to form 3-ethylenedioxy- 17cc hydroperoxy 16cc methyl-18-nor-pregnane-11,20- dione, reducing the latter to form 3-ethylenedioxy-16umethyl-18-nor-pregnane-17a-ol-11,20-dione, hydrolyzing the latter under acidic conditions to form 16a-methy1-18- nor-pregnane-lh-ol-SJ1,20-trione, reacting the latter with bromine to form 4,8-bromo-16a-methyl-18-nor-pregnane-17ot-o1-3,11,20-trione, dehydrobrominating the said 4B-bromo-steroid to form 16u-methyl-18-nor-A -pregnene-17a-0l-3,11,20-trione, introducing a hydroxyl group in the 21-position of the latter to form 16a-methyl-18- nor-cortisone and recovering the latter. The 16a-methyl- 18-nor-cortisone may be esterified in the 21-position by reacting the said cortisone with an esterifying agent such as an acid anhydride or acid halide.

16a-methyl-18-nor-pregnane-17a-ol-3J 1,20-trione may also be produced by reacting 3-ethylenedioXy-16a-rnethyl- 18-nor-pregnane-11,20-dione with acetic acid anhydride to form 3-ethylenedioxy-16a-rnethyl-20-acetoxy-18-n0r- A -pregnene-11-one reacting the latter with a peracid such as perbenzoic acid to form 3-ethylenedioxy-16amethyl-17,20-epoxy-20-acetoxy-18-nor pregnane-ll-one and subjecting the latter to acid hydrolysis to form 16mmethyl-18-nor-pregnane-17ot-ol-3,11,20-trione.

The introduction of the ZI-hydroxy group may be performed chemically by reacting 16a-methyl-18-nor-A pregnene-17a-ol-3,11,20-trione with iodine in the presence of a mixture of calcium chloride and calcium oxide to form the corresponding 21-diiodo derivative of the said steroid, reacting the latter with an alkali metal salt of a lower alkanoic acid to form the corresponding 21- acyloxy derivative of said steroid and hydrolyzing the latter to the corresponding ZI-hydroxy steroid. The 21- hydroxy steroid may also be formed by the action of diastases secreted by microorganisms such as ColletO- trichum lindemuthianum (ATCC 12,611) as described in U.S. Patent No. 2,805,978.

A preferred mode of the process of the invention comprises reacting 3-ethylenedioXy-16a-methy1-18-nor-pregnane-11,20-dione with oxygen in the presence of potassium tertiary butylate at room temperature to form 3- ethylenedicxy 17a hydroperoxy 16a methyl 18- nor-pregnane-l1,20-dione, reacting the latter with zinc and acetic acid to form 3-ethylenedioxy-16a-rnethyl-l8- nor pregnane-17wol-11,20-dione, hydrolyzing the latter with hydrochloric acid at reflux temperatures to form l6a-methyl-1S-nor-pregnane-lh-ol-L1LZO tIione, reacting the latter with bromine in acetic acid to form 45- bromo 16oz methyl 18 nor pregnane 17oz 01- 3,l1, 20- tri0ne, dehydrobrorninating the latter with a miX ture of lithium bromide and lithium carbonate to form 160a methyl l8 nor A pregnene -17u ol 3,11,20- trione, introducing .a hydroxyl group in the 21-position of the latter to form 16u-rnethyl-l8-nor-cortisone and recovering the latter. The reaction schemes are outlined in Table I.

wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms.

The starting material, S-ethylenedioxy-l6a-methyl-18- nor-pregnane-1 1,20-dione, is prepared by reacting 3-ethylenedioxy-l8-nor-A -pregnene-l1,20-dione described by Velluz et all. in Comptes Rendus Acad. 80., vol. 250 (196), page 371, with a methyl magnesium halide in the presence of cuprons chloride.

In the following examples there are described sevmoo-0H3 eral preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

The melting points are instantaneous melting points as determined on the Maquenne block.

EXAMPLE I Preparation of 3-Ethylenedi0xy-16oc-Methyl-18- Nor-Pregnane-l1,20-Dine, II To 40 cc. of ethereal solution of methylmagnesium iodide prepared from 2.2 gm. of magnesium and 9.0 cc. of methylene iodide, there was added, after cooling to 0 C., 120 cc. of tetrahydrofurane without allowing the interior temperature to mount above C. A White precipitate was formed and after having cooled to 0 C., 500 mg. of cuprous chloride were added in two p rtions, cooling each time to 0 C., and then 14 gm. of 3- ethylenedioxy 18 nor A pregnene 11,20 dione in 65 cc. of tetrahydrofuran were introduced over several minutes under agitation. The reaction mixture was agitated for a period of forty-five minutes, then poured into a mixture of 300 gm. of ice and gm. of ammonium chloride. After decantation, the solvents were removed under vacuum.

The residue comprising 3-ethylenedioXy-16a-methyl l8-nor-pregnane-11,20-dione crystallized. The aqueous phase resulting from the decantation was extracted with ether and the said pregnane as vacuum filtered was redissolved in combined ethereal extracts. The ethereal solution was washed with N/lO hyposulfite, then with water, dried over magnesium sulfate, passed in the carbon black and concentrated to a small volume. The product crystallized. Hexane was added, the ether was removed, the solution was iced, vacuum filtered, washed with hexane and dried. 12.4 gm. of 3ethylenedioxy- 16a-methyl-18-nor-pregnane-11,20-dione were obtained (being a yield of 85%) having a melting point of 148- 150 C. and a specific rotation [a] =+32- '-2 (c.=1% in chloroform). The product was soluble in alcohol, acetone, benzene, chloroform, slightly soluble in ether, hexane, insoluble in water.

Analysis.-C H O molecular weight=374.50. Calculated: C, 73.76%; H, 9.15%. Found: C, 73.9%; H, 9.1%.

This compound is not described in the literature.

EXAMPLE II Preparation of the Acetate of 16u-Methyl-18-N0r- Cortisone Step A.Preparati0n of 3-ethylenedioxy-J(fa-methyl- 7a-hydr0per0xy-18-nor-pregnane-11,20-ai0ne.2 gm. of potassium were dissolved in 170 cc. of tertiary butanol under agitation and an atmosphere of nitrogen. The mixture was cooled to 25 C. and 10 gm. of 3-ethylenedioxy- 16a-methyl-l8-nor-pregnane-11,20-dione were introduced. Oxygen was bubbled into the mixture for a period of forty-five minutes until the absorption of about 650 cc. of oxygen. A solution of 3-ethylenedioxy-17a-hydroperoxy-16a-methyl-18-nor-pregnane-11,20-dione was thus obtained.

Step B.-Preparation of 3-ethylenedi0xy-16a-methyl- 18-n0r-pregnane-1 7a-ol-11,20-dione.-To the refrigerated solution obtained in Step A were added 60 cc. of acetic acid and then 20 gm. of zinc. The mixture was agitated for a period of twenty minutes at room temperature, then heated to 60 C. for a period of fifteen minutes. The

.zinc was filtered, water was added and the organic solvents were eliminated by distillation. After alkalinization by addition of sodium hydroxide solution, the mixture was extracted with ether. The ethereal solution was washed with water, dried, evaporated to dryness and 3- ethylenedioxy-16a-methyl-18 nor pregnane 17a-ol- 11,20-dione was obtained as a residue. was used as such for the next step of the synthesis.

This compound Step C.-Preparati0n of 16a-methyl-18-n0r-pregnane- 17ct-ol 3,11,20-trione.---The compound prepared in Step B was dissolved in 60 cc. of acetone and 12 cc. of 5 N hydrochloric acid were added thereto. The mixture was heated to reflux for a period of five minutes, 20 cc. of water were added and the acetone was removed under vacuum. 16a-methyl-18-nor-pregnane-17a ol 3,11,20- trione crystallized. The crystals were vacuum filtered washed with water, dissolved in methylene chloride, treated with animal black, filtered and concentrated to a small volume. On the addition of hot ether, 16a-methyl- 18-nor-pregnane-17a-ol-3,11,20-trione precipitated. The crystals were vacuum filtered to give 4.32 gm. of product (being 45% with reference to 3-ethylenedioxy-l6ctmethyl-l8-nor-pregnane-l1,20-dione), melting at 202 C. and directly utilizable for the next step of the synthesis.

By evaporation of the mother liquors, it was possible to recover 1.5 gm. of 16a-methyl-lS-nor-pregnane- 3,1 1,20-trione.

For analysis, the 16a-methyl-18-nor-pregnane-17a-ol- 3,11,20-trione was purified by recrystallization from methylene chloride to give a sample melting at 204206 C. and having a specific rotation [a] =|-21 (c.=1% in chloroform). The product occurred in the form of colorless crystals. It was very soluble in chloroform, soluble in alcohol and acetone and slightly soluble in ether and insoluble in water.

Analysis. C I-1 0 molecular weight 346.45. Calculated: C, 72.80%; H, 8.73%. Found: C, 72.6%; H, 8.8%.

The infrared spectra confirmed the presence of a hydroxyl by a band at 3607 cmr This compound is not described in the literature.

Step D.--Preparali0n of 4,8-br0m0-16a-metlzyl-18-n0rpregnane-J7a-ol-3,11,20-trione.4 gm. of l6a-methyl-l8- nor-pregnane-17a-ol-3,l1,20-trione were dissolved in cc. of anhydrous chloroform. 9 cc. of acetic acid were added and then 11.5 cc. of a solution cooled to -60 C. of bromine in acetic acid were introduced drop by drop. The solution was prepared from 14.55 gm. of bromine, 7.3 gm. of hydrobromic acid and a suflicient quantity of acetic acid in order to give a volume of 90 cc. The reaction mixture was agitated for a period of thirty minutes at 60 C. and then 2.8 gm. of sodium acetate containing 3 mols of water in 15 cc. of water were added thereto. The mixture was poured onto a mixture of water and ice and extracted with chloroform. The extracts were washed with a solution of sodium bicarbonate and water, then dried over magnesium sulfate. The solution was concentrated to a small volume, vacuum filtered and 3.8 gm. (being 80%) of 4/3-bromo-16a-methyl-18-nor-pregnane-17a-ol-3,11,20-trione were obtained which was utilized in the raw state for the next step of the synthesis.

This compound is not described in the literature.

By treatment with zinc and acetic acid, 0.44 gm. of the 16ot-methy1-18-nor-pregnane-17a ol 3,11,20 trione were recovered from the mother liquors.

Step E.Preparati0n of l6a-methyl-l8-nor-A -pregnene-17a-0l-3,11 ,20-trz'0ne.3.8 gm. of 4fi-bromo-16amethyl-18-nor-pregnane-17a-ol-3,11,20-trione were introduced into 38 cc. of anhydrous dimethlformamide. 2 gm. of lithium bromide and 1 gm. of lithium carbonate were added and the mixture was heated under agitation and an atmosphere of nitrogen to C. for a period 'of forty minutes. After cooling and addition of water Calculated: C, 73.22%; H, 8.19%.

" Tap water to make 1,000'cc.

7 Analysis. C I-1 molecular weight 344.44. Found: C, 73.0%.;

Ultraviolet spectra: A 238 m e=15',1'00.

This compound is not described in the literature.

Step F.Preparation of 16ot-methyl-2I-dii0d0-18-rwr- A4-pregnene-17m-ol-3J1,20-tri0ne.- 850 mg. of 16amethyl-lS-nor-N-pregnerie-l704-0143,l 1,20-trione were introduced in 7.5 cc. of methanol. '850 mg. of quick lime and 3 cc. of methanol containing 10% calcium chloride were added and the mixture was cooled to -10 C. To the mixture were added 1.27 gm. of pulverized iodine and the mixture was agitated in a closed vessel for a period of one hour: The draw 2lv-diiodo-l6wmethyl-l8-nor- A -pregnene-17a-ol-3J1,20-ttrione formed was vacuum filtered. The residue was washed with a dilute solution of acetic acid and with water and utilized without purification for the next step of the synthesis.

This compound is not described in the literature.

Step G.-Preparati0n of the acetate 0 16a-methyl-18- n0r-cortis0ne. The 21-iodo derivative prepared in 'Step F was dissolved in acetone. 0.2 cc. of acetic acid and 3 gm. of potassium acetate were added. The mixture was heated to reflux for a period of one hour and a half and then 10 cc. of water were added and the acetone was removed under vacuum. The acetate of l6m-methyl-18-norcortisone crystallized. The product was vacuum filtered, washed with water, dried, and taken up by a mixture of acetic acid and acetone. 300 mg. of zinc were added. The mixture was refluxed for a period of several minutes. The mixture was treated with animal black, filtered, concentrated to a small volume and vacuum filtered. 'The product was recrystallized from aqueous acetone to give a product melting at 247-248 C. and having a specific rotate .[a]' =+ll5:2 (c.=1% in chloroform). The product occurred in the form of square leaflets, very soluble in chloroform, soluble in acetone, very slightly soluble in alcohol and insoluble in water and ether.

Analysis.-C H o0 molecular weight=402.47. Calculated: C, 68.63%; H, 7.51%. Found: C, 68.5%; H,

Ultraviolet spectra: A 238 mu, e=15,000.

This compound is not described in the literature.

EXAMPLE III Preparation of 16a-Methyl-18-Nor-Cortis0ne 1 gm. of the acetate of, mot-methyl-18 nor-cortisone produced in Example II was introduced into 10 cc. of methanol. 0.1 'cc. of a normal solution of sodium methylate in methanol was added and the mixture was heated at reflux for aperiod of fifteen minutes under nitrogen; After neutralization and dilution with an equal volume of water, the methanol was removed under vacuum and the 16x-methyl-l8-nor-cortisone was recovered.

This compound is not described in the literature.

um containing 2% of saccharose and 20% of potato extract. The conidies were collected in distilled water. The

suspension obtained was used to sterilely inoculate a 1- liter Erlenmeyer flask containing 100 cc. of a medium composed as follows: Y a

1 7 Grams Pure glucose g 10 "Malt extract Soy bean meal Sodium chloride 5 Dry cornv steep V 7 V 5 Calcium carbonate 1 3,11,20-trione.

01-1 1,20- dione.

7.0 by potassium hydroxide and it was sterilized by heating thirty minutes to a temperature of 120 C. After five days of culturing at 25 on a shaking apparatus strokes per minute, 8 cc. stroke), 10 cc. of an acetonic solution containing 1% of 16umethyl- 18-nor-A -pregnene-17u-ol-3,11,20-trione obtained according to Example II, were added to 1,000 cc. of culture. A new incubation of twenty-four'hours gave 16a-methyl-l8-nor-cortisome as is evidenced by chromatographic determinations on paper which were effected as follows on 50 cc. of culture broth.

The broth was filtered and the mycelium washed two times with 5 cc. of acetone which was added to the filtrate. The mycelium was next extracted with 2 aliquots of 50 cc. of chloroform and the preceding filtrate was extracted with these cc. of chloroform. Then the extractions were made again two times with 20 cc. of chloroform each time. The chloroformic extracts were combined and were washed first with an aqueous solution of sodium bicarbonate, then with water and dried over magnesium sulfate. The solutions were then evaporated to dryness under vacuum. The residue was taken up with 1 cc. of methanol and subjected to paper chromatography. Previous to the chromatographic adsorption, the paper strip was immersed in a solution of 30% propylene glycol.

After allowing it. to drip, the steroid is chromatographed with toluene saturated with propylene glycol. and a development of eight to fifteen hours is effected. The detection of spots was made by the color reaction of Mader et al. (Anal. Chem. 1952, 24, p. 666) with triphenyl tetrazolium chloride which gives a red-coloration on a white foundation with steroids possessing the ketol function RCOOH OH.

Various modifications of the process of the invention may be made without departing from, the spirit or scope thereof, and it is to-be understood that the invention is to be limitedonly' as defined in the-appended claims.

Weclaim:

1. 3-ethylenedioxy 16a methyl-l7u-hydroperoxy-l8- nor-pregnane-l1,20-dione.

2. 3-ethylenedioxy 16a methyl-l8-nor-pregnane-l7a- 3. 16a-rnethyl 18 nor-pregnane-17a-ol-3,l1,20-trione.

4. 45 bromo 16o: methyl-18-nor-pregnane-17a-ol- 5. 16h methyl l8 nor-M-pregnene-lh-ol-3,11,20-

trione. I V 7 6-. 16a-methyl-2l-diiodo l8. nor-A -pregnene-17'a-ol- 3,11,2Q-trione.

7. A process for the preparation of compounds having 'the formula 7 "-on *Lon.

wherein R is selected from the group consisting of hydrogen and' an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms which comprises oxidizing 3- ethylenedioxy 16oz methyl-1 8-nor-pregnane-ll,20-dione with oxygen in the presence of an alkali metal tertiary -butylate ,to form 3-ethylenedioxy l7a-hydroperoxy-16mmethyl-lS-nonpregnane-l1,20-dione, reducing the latter 'to form 3gethylenedioxyrl6a-methyl-l8-nor pregnane-17aol-ll,20-dione, hydiolyzing the latter under-acidic conditions to form 16ot-methyl-l8-nor-pregnane-17br-ol-3,11,20- trione, reacting the latter with bromine to form ip-bromol6qc-methyl-18-nor-pregnane-17a-ol-3,l1,20-triohe, dehy- Z drobrominating the latter to form I6a-methyl-18-nor-A pregnene-l7a-ol-3,l1,20-trione, introducing a hydroxyl group in the 21-position by microbiological means with Colletotrichum lindemuthianum to form 16a-methyl-18- nor-cortisone and recovering a compound of the above formula.-

8. The process of claim 7 wherein the oxidation is reflected with oxygen in the presence of potassium tertiary .butylate.

9. The process of claim 7 wherein the reduction is effected with zinc and acetic acid.

10. The process of claim 7 wherein the dehydrobromination is effected with a mixture of lithium bromide and lithium carbonate.

11. A process for the preparation of a compound having the formula CHnOR E 0 on OH I mam one wtih oxygen in the presence of potassium tertiary butylate to form 3-ethylenedioxy-17a-hydroperoxy-16amethyl-lS-nor-pregnane-l1,20-dione, reducing the latter with zinc and acetic acid to form 3-ethylenedioxy-16amethyl-18-nor-pregnane-l7a-ol-11,20-dione, hydrolyzing the latter under acidic conditions to form 16u-methyl-18- nor-pregnane-17a ol-3,11,20-trione, reacting the latter with bromine in acetic acid to form 4B-bromo-l6a-methyl-18- nor-pregnane-17u-ol-3,11,20 trione, dehydrobrominating the latter in the presence of a mixture of lithium bromide and lithium carbonate to form 16tz-methyl-l8-nor-A pregnene-17a-ol-3,l1,20-trione, reacting the latter with iodine in the presence of a mixture of calcium oxide and calcium chloride to form 2l-diiodo-l6a-methyl-l8-nor-A pregnene-17a-ol-3,l1,20-trione, reacting the latter with an alkali metal salt of a lower alkanoic acid to form 21-acyloxy-16a-methyl 18 nor-N-pregnene-l7a-o1-3,11,20-trione, hydrolyzing the latter to form 16a-methyl-18-norcortisone and recovering a compound of the above formula.

12. A process for the preparation of a compound having the formula onion n =0 0 '--on on L 19 with oxygen in the presence of potassium tertiary butylate to form 3-ethylenedioxy-l7a-hydroperoxy-l6tx-methyl-18- nor-pregnane-l1,20-dione, reducing the latter with zinc and acetic acid to form 3-ethylenedioxy-16a-methy1-18- nor-pregnane-17oto1-l1,20-dione, hydrolyzing the latter under acidic conditions to form 16ot-methyl-18-nor-pregnane-l7a-ol-3,l1,20-trione, reacting the latterwith bromine in acetic acid to form 4B-bromo-16ct-methyl-18-norpregnane-17a-ol3,l1,20-trione, dehydrobrominating the latter in the presence of a mixture of lithium bromide and wherein R is selected from the group consisting of hydro- 7 gen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms which comprises oxidizing 3- ethylenedioxy-16a-methyl 18 nor-pregnane-11,20-dione with oxygen in the presence of an alkali metal tertiary butylate to form 3-ethylenedioxy-l7u-hydroperoxy-l6amethyl-18-nor-pregnane-11,20-dione, reducing the latter to form 3-ethylenedioxy-l6a-methyl-l8-nor-pregnane-17otol-11,20-dione, hydrolyzing the latter under acidic conditions to form l6a-methyl-18-nor-pregnane-17a-ol-3,11,20- trione, reacting the latter with bromine to form 4B-bromol6a-methyl l8 nor-pregnane-l7a-ol-3,l1,20-trione, dehydrobrominating the latter to form 16oc-methyl-18-nor- ,A -pregnene-17u-ol-3,11,20-trione, reacting the latter with iodine in the presence of a mixture of calcium oxide and calcium chloride to form 21-diiodo-16u-methyl-18-nor- A -pregnene-17 u-ol-3,11,20-trione, reacting the latter with an alkali metal salt of a lower alkanoic acid to form 21- acyloxy-16a-methyl 18 nor-A pregnenel7a-ol-3,11,20- tri one and hydrolyzing the latter to form 16a-methyl-18- nor-cortisone.

OTHER REFERENCES Arth et al.: I.A.C.S., June 20, 1958, page 3160'. 

5. 16A - METHYL -18 - NOR-$4-PREGNENE-17A-OL-3,11,20TRIONE. 